Rhombencephalosynapsis and Gómez-López-Hernández Syndrome (including MN1-Related MCTT-CEBALID)

Hindbrain malformation in which the cerebellar hemispheres are fused across the midline with total or partial absence of the vermis; it occurs in isolation, as the core of Gómez-López-Hernández syndrome (with non-scarring alopecia and trigeminal anaesthesia), associated with VACTERL features or with posterior holoprosencephaly, and as an atypical form in the syndrome caused by C-terminal truncation of MN1.

Literature and regulatory information updated: 28 October 2026.

0. Initial Reference Table

Rhombencephalosynapsis (RES) is treated as a class: the cerebellar malformation is the common element and the entities are distinguished by the extracerebellar findings and, in one of them, by the molecular cause. The table summarises the five entities in scope; the rhombencephalosynapsis variant with VACTERL features (vertebral, anal, cardiac, tracheo-oesophageal, renal and limb) and hydrocephalus and pontocerebellar hypoplasia type 1B with rhombencephalosynapsis are summarised.

The two entities with their own OMIM entry have different status: GLHS (601853) is classified as a Mendelian phenotype whose molecular basis has not been identified, with no associated gene, whereas MCTT, registered under the title CEBALID (618774), is linked to heterozygous MN1 variants (gene 156100), with autosomal dominant inheritance [4, 6, 14]. The association of GLHS with chromatin-regulation genes, which appears in some compilations of genetic diseases, has no support in any of the sources consulted: the aetiology of the syndrome remains unknown [1, 5, 11, 13].

1. Introduction

1.1. Founding descriptions

The first description of a malformation with fusion of the cerebellar hemispheres dates back to 1914, at the autopsy of a 28-year-old man; since then more than 150 individuals with rhombencephalosynapsis have been published [13]. The syndrome that would come to bear the names of two paediatric neurologists of Hispanic origin, Manuel Gómez and Arturo López-Hernández, was delineated before the nature of the underlying brain malformation was known [10, 39]. In 1979, Gómez, at the Mayo Clinic, described a girl with brachycephaly, hypertelorism, convergent strabismus, interstitial keratitis, bilateral facial analgesia with absent corneal reflexes and an area of congenital alopecia in the occipital and posterior parietal region; the child had generalised hypotonia early in life and, at 4 years and 9 months, moderate intellectual disability and a severe cerebellar deficit with gait and truncal ataxia, without involvement of other cranial nerves [2]. Gómez proposed the designation "cerebellotrigeminal and focal dermal dysplasia" and interpreted the picture as an arrest in the development of the ectoderm that gives rise to the alar plate of the rhombencephalon, the overlying epidermis, the trigeminal motor nucleus and the trigeminal placodes [2].

In 1982, López-Hernández described two unrelated Mexican girls with craniosynostosis, ataxia, trigeminal anaesthesia and an area of parietal alopecia, associated with an anomaly of fusion between the pons and the vermis that he called "atresia of the fourth ventricle"; the anomaly was seen only on computed tomography (CT) and correlated with the ataxia, and both children had midface hypoplasia, bilateral corneal opacities, low-set ears, intellectual disability and short stature [40]. The nature of the malformation, a rhombencephalosynapsis, was recognised only with the MRI of later patients [10]. In 1997, the description of three new Brazilian patients, which brought the total to seven, consolidated the term "cerebello-trigemino-dermal dysplasia" and drew attention to underdiagnosis [3].

1.2. Growth of the case series

The published GLHS case series grew slowly: 7 documented cases in 2000 [41], 7 to 15 cases in 2007–2008 depending on the inclusion criteria [26, 42], 19 in 2009 [43], 21 in 2010 [44], 30 in 2013 [29], 34 in 2014 [45], 35 in 2017, with the first case from the Indian subcontinent [46], about 57 in a 2020 systematic review [19] and about 60 in 2024 [24]. The count of 36 cases used by Orphanet is sourced from the 2017 Indian report [18, 46], and the 8th edition of Smith's refers to "more than 30" [1]. These counts measure cases published under the GLHS label, not the frequency of the syndrome, and depend on the definition adopted by each author.

1.3. From the named syndrome to the rhombencephalosynapsis spectrum

The systematic study of rhombencephalosynapsis cohorts, above all the Seattle cohort assembled by W. B. Dobyns, D. Doherty and colleagues, changed the way GLHS is viewed. Ishak and colleagues, with the MRI of 42 patients, proposed in 2012 a severity scale for the malformation and showed its association with aqueductal stenosis, fusion of the midbrain tectum and forebrain anomalies [47]. In the same year, Tully and colleagues described 53 patients, in whom alopecia occurred in 33, trigeminal anaesthesia in 3, VACTERL features in 14 and holoprosencephaly with aventriculy in 2, with considerable overlap between groups; only 17 of the 53 could be classified unambiguously into a specific syndrome [10]. The authors proposed that alopecia, the "GLH-type" craniofacial features and trigeminal anaesthesia be considered anomalies associated with rhombencephalosynapsis rather than components of a named syndrome, by analogy with the holoprosencephaly spectrum, in which the brain malformation and the craniofacial features form a continuum [10]. In 2018, the same team reviewed 115 individuals and the genomic investigation of 59 probands, without identifying a recurrent gene [13].

In parallel, the clinical delineation of GLHS evolved through successive proposals of criteria. Sukhudyan and colleagues, with six patients from Armenia and Switzerland without trigeminal dysfunction, considered rhombencephalosynapsis and alopecia the only constant and therefore mandatory findings, and noted that the designation "cerebello-trigemino-dermal dysplasia" could be misleading [44]. Rush and colleagues proposed formal criteria in 2013 [29], and Perrone and colleagues, with 13 Brazilian patients, proposed in 2021 criteria that do not require rhombencephalosynapsis [11]. A case with alopecia and trigeminal anaesthesia without rhombencephalosynapsis had been described in 2012 [19, 48].

1.4. Discovery of the first monogenic cause of rhombencephalosynapsis

In 2020, two groups independently described a syndrome caused by de novo truncating variants in the terminal exon of the MN1 gene: Mak and colleagues, with 23 individuals and an atypical form of rhombencephalosynapsis in 8 of the 10 with imaging available [30], and Miyake and colleagues, who demonstrated in cellular studies a gain-of-function effect of the truncated protein [49]. The entity was named MN1 C-terminal truncation syndrome (MCTT) and, in OMIM, given the acronym CEBALID, adopted as the main title of the entry, with MCTT as an alternative designation [6]; the corresponding GeneReviews chapter was published in August 2020 [5]. It is the first definitive genetic cause of a form of rhombencephalosynapsis, although the malformation in MCTT is partial and morphologically distinct from the classic form [5, 30].

1.5. Current classifications

The Orphanet classification of July 2026 organises the class into two branches. Isolated rhombencephalosynapsis (ORPHA:59315) is an isolated cerebellar malformation. The group "syndromic rhombencephalosynapsis" (ORPHA:729538), placed under syndromes with cerebellar malformation as a major feature, has as members GLHS (ORPHA:1532), VACTERL with hydrocephalus (ORPHA:3412) and facial dysmorphism–intellectual disability–rhombencephalosynapsis syndrome (ORPHA:693549, which corresponds to MCTT). The group "genetic syndromic rhombencephalosynapsis" (ORPHA:730699), in the classification of rare genetic diseases, includes only VACTERL with hydrocephalus and MCTT: GLHS is not included in the genetic branch, consistent with the absence of a known cause [17, 18, 22, 23].

1.6. Definitions of the entities in scope

Rhombencephalosynapsis is the congenital, complete or partial fusion of the cerebellar hemispheres, the dentate nuclei and the middle cerebellar peduncles, with complete or partial absence of the vermis; it may occur in isolation or accompanied by other brain malformations [17]. It is called isolated when there is no alopecia, trigeminal anaesthesia, VACTERL features or holoprosencephaly; in the Seattle cohort, rhombencephalosynapsis was the only brain malformation in 24% of individuals [13].

GLHS is defined by Orphanet as a neurocutaneous syndrome with the association of anomalies of the cerebellum (rhombencephalosynapsis), the cranial nerves (trigeminal anaesthesia) and the scalp (alopecia), to which are added craniosynostosis, midface hypoplasia, bilateral corneal opacities, low-set ears, short stature, moderate intellectual disability and ataxia [18]. Smith's includes trigeminal anaesthesia in the subtitle of the syndrome and in the original description, but also lists it among the occasional anomalies, and considers that only rhombencephalosynapsis and alopecia are consistently present [1]. This divergence reflects the difference between the founding cases, selected by the triad, and the later series, ascertained through the brain malformation.

MCTT is the neurodevelopmental and craniofacial syndrome caused by variants that truncate the C-terminal region of the MN1 protein and escape nonsense-mediated messenger RNA decay (NMD) [5, 30]. Rhombencephalosynapsis with VACTERL features groups patients with vertebral segmentation defects and renal, cardiac, anorectal or radial ray anomalies; when hydrocephalus is present, it overlaps with VACTERL with hydrocephalus (ORPHA:3412) [9, 10]. Rhombencephalosynapsis with posterior holoprosencephaly and aventriculy is a rare form in which the cerebral hemispheres are fused with occipital predominance and the lateral and third ventricles are absent [10].

2. Molecular Genetics and Pathophysiology

2.1. Embryology of the cerebellum and the trigeminal territory

The cerebellum derives from rhombomere 1 and the trigeminal nucleus and ganglion are related to rhombomere 2; the boundary between the midbrain and the hindbrain is established at around 17 to 19 days of development, and the trigeminal ganglia become visible in the fourth week from the neural crest, the roof plate and the trigeminal placode, the latter located in the surface ectoderm that corresponds to the future temporal region [19]. All these primordia are of ectodermal origin, which offers an embryological explanation for the coexistence of rhombencephalosynapsis, trigeminal anaesthesia and temporal or parietal alopecia [2, 19]. The isthmic organiser, at the junction between the mesencephalon and the metencephalon, is defined by the expression of OTX2 and GBX2, and defects of this signalling centre have been proposed as the origin of the aqueductal stenosis associated with rhombencephalosynapsis [24, 52].

Ishak and colleagues found that the severity of rhombencephalosynapsis correlates with fusion of the cerebellar tonsils and with midbrain anomalies, such as aqueductal stenosis and midline fusion of the tectum, which supports a disturbance of dorsoventral patterning as the mechanism [47]. The neuropathological study of 40 fetuses led to the hypothesis of genes that regulate formation of the roof plate and of the midline cerebellar primordium at the junction between the midbrain and the first rhombomere [31]. Other hypotheses include underexpression of a dorsoventral patterning gene and loss of the cells of the anterior cerebellar anlage destined for the vermis [24]. Mesencephalosynapsis, or non-cleavage of the colliculi, often accompanies rhombencephalosynapsis: in a neuropathological series of 115 cases of fetal obstructive hydrocephalus between 15 and 41 weeks, it was present in 44 (38.3%), was associated with 67% of severe aqueductal pathologies and, in 75% of cases, coexisted with other central nervous system anomalies, including rhombencephalosynapsis and holoprosencephaly [53]. A 2026 neuropathological study showed that keratan sulphate proteoglycan is not expressed in the fetal cerebellum or in cerebellar dysgeneses, including rhombencephalosynapsis, which rules out its participation in the pathogenesis [54]. Rhombencephalosynapsis is not known in animals, either spontaneous or experimental, which limits the study of the mechanism [10].

Tully and colleagues interpreted the set of malformations as a developmental field defect: a biological pathway common to the cerebellum, the trigeminal ganglia, the skull, the face and focal areas of the scalp, which holoprosencephaly with aventriculy extends to the forebrain and VACTERL features to somitogenesis and the radial ray [10]. Aldinger and colleagues added as possible mechanisms the specification of vermian cell fates, mechanisms shared with the VACTERL association and a gene–environment interaction, by analogy with the vertebral defects in which partial loss of function of the Notch pathway combines with in utero hypoxia [13].

2.2. Arguments in favour of a genetic basis

The malformation is stereotyped, like holoprosencephaly or Joubert syndrome; it is consistently associated with other malformations of early embryonic origin; and it is not related to prematurity or to prenatal events, which, taken together, suggests a genetic basis [13]. However, familial recurrence is exceptional: in all the literature reviewed up to 2018 there were only two families with possible recurrence, a pair of sibling fetuses in a series of 40 fetuses [31] and two half-sisters with partial rhombencephalosynapsis, holoprosencephaly and an intragenic ZIC2 deletion [55], whose diagnosis of rhombencephalosynapsis was disputed and not confirmed by the Seattle team [10, 13]. Rhombencephalosynapsis occurred in at least four consanguineous families without recurrence, one of them with 10 unaffected siblings; six adults with rhombencephalosynapsis had 11 children, none with the malformation [13].

These data led to the hypothesis of dominant de novo variants, germline or mosaic. The existence of two discordant monozygotic twin pairs in the Seattle cohort is compatible with post-zygotic mosaicism, with an imprinting defect (for example, in the 11p15 region) or with prenatal vascular perfusion insufficiency [13]. The absence of recurrence in consanguineous families argues against autosomal recessive inheritance as a general explanation [13], although cases with consanguineous parents have led some authors to raise this hypothesis [45, 46].

2.3. The cause of Gómez-López-Hernández syndrome remains unknown

No source consulted identifies a gene for GLHS. Smith's (2022) and the MCTT GeneReviews chapter (2020) state that the cause is unknown and that all cases have been sporadic [1, 5], and Orphanet records the inheritance as "not applicable" [18]. The published molecular studies have all been negative or inconclusive, and none points to chromatin-regulation genes; the attribution of GLHS to a chromatin mechanism, present in some compilations of genetic diseases, has no support in the literature reviewed.

These studies have limits that prevent concluding that there is no genetic cause. DNA from blood or saliva does not detect post-zygotic variants restricted to the affected tissue, the exome does not assess non-coding variants or complex structural rearrangements, and the cohorts are small for a presumably heterogeneous disease [13]. Aldinger and colleagues proposed deep sequencing of skin from the areas of alopecia, long-read genome sequencing, RNA sequencing, international collaborations and prospective collection of prenatal exposures [13]. The ZIC1 case illustrates the importance of balanced structural variants, invisible to the exome [51].

2.4. Copy number variants and rearrangements

Rare, non-recurrent chromosomal rearrangements have been described in patients with rhombencephalosynapsis: 2q deletion; derivative chromosome der(10)t(2;10)(p25.3;q26.3); 14q12-q21.2 deletion; 16p11.2 and 16p13.11 deletions; a rearrangement involving 22q13.3 and 10q26.3; tetrasomy 9p; microduplication in 1p; and a microduplication in 7p, which the Tully 2012 table records as 7q [10, 13, 57]. In the 16p13.11 microdeletion, two candidate genes were studied by sequencing and in situ hybridisation, without confirmation [57]. De novo variants in CHAMP1 were associated with partial rhombencephalosynapsis in 1 of 5 individuals, without replication [13]. None of these changes establishes, by itself, a causal relationship with rhombencephalosynapsis.

2.5. MN1 and the C-terminal truncation syndrome

The MN1 gene (MN1 proto-oncogene, transcriptional regulator; HGNC:7180; OMIM 156100; reference transcript NM_002430.3) has only two exons and encodes a transcriptional co-regulator without homology to other proteins, which interacts with the transcription factors PBX1, PKNOX1 and ZBTB24 [5, 15, 30]. MN1 is required for craniofacial development: it induces expression of TBX22 in the developing posterior palate, which is needed for growth and medial fusion of the palatal shelves, and promotes maturation of calvarial osteoblasts [15]. The gene was originally identified from a balanced t(4;22) translocation [14, 15].

The cytoband of MN1 differs between sources: the OMIM entry for MCTT (last edited in 2023), GeneGuidance and the genomic location in ClinVar (GRCh38, chromosome 22, position 27,750,995 for the recurrent variant) place it at 22q12.1, whereas the genetic information table of the 2020 GeneReviews chapter gives 22q12.3-qter [5, 6, 15, 16]. The location at 22q12.1 corresponds to current genomic coordinates; the designation 22q12.3-qter reflects an older cytogenetic mapping that no longer matches what OMIM gives today.

All MCTT-causing variants lie in the terminal exon (exon 2) or at the 3' end of exon 1, so they escape NMD and produce a truncated protein; escape from NMD was confirmed in fibroblasts from three individuals [5, 30]. In cells, deletion of the C-terminal region increased protein stability, reduced cell proliferation and increased nuclear aggregation of MN1 [49]. The truncated protein loses binding to ZBTB24 and to the E3 ubiquitin ligase RING1, which reduces its turnover through the ubiquitin–proteasome pathway and dysregulates target genes; the authors consider an alteration of phase separation possible [5, 49]. In detail, co-immunoprecipitation of the protein with p.(Arg1295Ter) showed reduced interaction with ZBTB24, absence of binding to RING1 and to the transcription factor E2F7 and, conversely, binding to partners that the normal protein does not recruit, such as MEIS1 and PBX2; the mutant protein retained the ability to activate transcription and formed larger and less soluble aggregates in HeLa cells, and the transcriptome of the carrier's lymphoblastoid cells revealed genes with increased expression and others with decreased expression. The increased fraction of intrinsically disordered regions after loss of the C-terminal segment is the authors' argument for the phase separation hypothesis [6, 49]. The mechanism is a probable gain of function mediated by the truncated protein, not haploinsufficiency [5, 30]. No causal intragenic deletions or duplications have been described [5, 15].

The variants were normalised in VariantValidator to transcript NM_002430.3; GeneReviews uses NM_002430.2, with identical c. numbering [5, 60]. The difference between 8 of 21 and 9 of 25 for the recurrent variant results from different denominators (probands of one series versus individuals of the two founding series). The conflicting classification of c.3883C>T in ClinVar contrasts with the de novo recurrence in probands with a concordant phenotype and with the functional confirmation of NMD escape; the conflict should be read in the context of the record, which aggregates submissions for different conditions, and does not invalidate the association demonstrated in the published series [16, 30]. No genotype–phenotype correlations have been identified [5].

2.6. MN1 allelic disorders

Truncating variants in the N-terminal third of MN1, predicted to undergo NMD, cause a partially overlapping but distinct phenotype: conductive hearing loss, speech disorder and mild developmental delay, without intellectual disability, without the facial gestalt of MCTT and, in one of the individuals studied, without a persistent trigeminal artery [5, 30]. In the original series, this milder group comprised three individuals with N-terminal variants and two with whole-gene deletion, all de novo; MRI, performed in three of the five, was normal in two and showed platybasia in the third, and none had rhombencephalosynapsis [6, 30]. Contiguous gene deletions that include MN1, and one case of deletion of MN1 alone, are associated with cleft palate or high-arched palate, micrognathia or retrognathia, hypertelorism, low-set or dysplastic ears, hypoplastic corpus callosum, mild to moderate delay and intellectual disability with speech delay, without rhombencephalosynapsis [5]. These microdeletions have been related to craniofacial syndromes such as Toriello-Carey syndrome [8].

MN1 is also a proto-oncogene. Somatic fusions occur in myeloid neoplasms with t(12;22)(p13;q12) and MN1–ETV6 fusion (12 cases reviewed) [61] and in high-grade paediatric neuroepithelial tumours with MN1–BEND2 fusion [62]; meningioma is associated with the gene [8, 15]. No cancer has been described in patients with MCTT, and the somatic fusions do not imply increased cancer risk in the germline syndrome [5].

2.7. Other rare monogenic causes associated with rhombencephalosynapsis

ZIC1 (3q24) encodes a cerebellar zinc-finger transcription factor. Heterozygous loss of function is associated with Dandy-Walker malformation, and gain of function with craniosynostosis, brain anomalies, dysmorphism and learning difficulties [51]. In a boy with clinically suspected GLHS (bicoronal craniosynostosis, rhombencephalosynapsis, temporal alopecia and dysmorphism), a de novo inversion in 3q with a breakpoint 7 kb downstream of the 3' untranslated region of ZIC1 was located by long-read sequencing; the authors attributed the picture to transcriptional dysregulation of ZIC1 through a position effect, a hypothesis not demonstrated functionally [51]. Two siblings with a frameshift variant of ZIC1 at the end of exon 3, absent in the parents (implying gonadal mosaicism), had microcephaly, agenesis of the corpus callosum, brachycephaly with a small posterior fossa, cerebellar and pontine hypoplasia, scoliosis and tethered cord, and one of them an apparent partial rhombencephalosynapsis; the abnormal transcript was stable and escaped NMD [63].

In pontocerebellar hypoplasia type 1B (PCH1B), two sibling fetuses of Roma origin, homozygous for the founder variant EXOSC3 NM_016042.4:c.92G>C p.(Gly31Ala), had fetal akinesia, microlissencephaly, loss of spinal motor neurons and rhombencephalosynapsis; in typical PCH1B, the lesions affect the hemispheres with relative sparing of the vermis, the opposite of rhombencephalosynapsis [50]. According to the same authors, the association of rhombencephalosynapsis and microlissencephaly had previously been described only with a de novo missense variant in ADGRL2 [50]. Rhombencephalosynapsis also appears among the occasional anomalies of Finlay-Marks syndrome (scalp–ear–nipple), autosomal dominant through KCTD1 variants [64], and was described in a fetus with megalencephaly–capillary malformation–polymicrogyria syndrome and hydrops, in a conference abstract [65].

2.8. Environmental and maternal factors

Interviews with the mothers of the Seattle cohort identified no obvious exposures to medicines, high fever, drugs, alcohol, serious illness or trauma; several had pre-existing diabetes or had used assisted reproduction [13]. The two patients with posterior holoprosencephaly and aventriculy in the 2012 cohort and similar cases described by other authors were children of mothers with pre-existing diabetes, a known risk factor for holoprosencephaly [10]. The first patient with GLHS studied molecularly had been exposed to misoprostol about three weeks after conception; misoprostol is associated with scalp anomalies, Moebius sequence and limb reduction defects through vascular disruption, but the authors considered that the vascular hypothesis does not apply to rhombencephalosynapsis on current evidence, and an isolated case does not demonstrate causality [19]. The review of 57 patients recorded isolated reports of maternal abuse of various substances, cannabis exposure and in vitro fertilisation [19].

2.9. Penetrance, expressivity and modifiers

For rhombencephalosynapsis and GLHS, penetrance cannot be measured because there is no known cause. Expressivity is variable: the same cerebellar malformation coexists with normal cognition or profound intellectual disability, and alopecia and trigeminal anaesthesia may be very mild [13, 26]. In MCTT, the variants are almost always de novo and there are no penetrance data in families; a mosaic father of two affected children had only mild features, such as slightly dysplastic ears and a high, narrow palate [5, 30].

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and ascertainment biases

The natural history of rhombencephalosynapsis rests on three types of sources with different biases. The case series published under the GLHS label were selected by the clinical triad and overestimate trigeminal anaesthesia; the cohorts ascertained through the brain malformation, above all the Seattle cohort (53 patients in 2012 and 115 in 2018, from a database of more than 6800 patients with brain malformations), give frequencies more representative of the spectrum; and the prenatal and neuropathological series concentrate the most severe forms, with hydrocephalus and associated malformations [10, 13, 31, 66]. The difference in the frequency of trigeminal anaesthesia, 3 of 50 patients in the 2012 Seattle cohort against 17 of 21 in the case review by Sukhudyan, was attributed precisely to this bias [10]. The available data mainly describe treated patients (with cerebrospinal fluid shunting, craniosynostosis surgery and rehabilitation); there is no natural history series without intervention.

3.2. Frequency of findings in the rhombencephalosynapsis spectrum

In the 2018 Seattle cohort, the 115 individuals were distributed as follows: 28 with rhombencephalosynapsis without alopecia or VACTERL features, 44 with alopecia, 14 with alopecia and trigeminal anaesthesia, 25 with VACTERL features (with or without alopecia), 2 with holoprosencephaly and VACTERL features and 2 with insufficient data [13]. Extracerebral anomalies included vertebral defects in 12 (10%), rib anomalies in 10 (9%), cardiac in 17 (15%), limb in 8 (7%), renal in 7 (6%) and genitourinary or gastrointestinal in 4 (3%); unilateral craniofacial microsomia occurred in 3 to 4 patients, depending on whether counted from the text or from the table notes, and tethered cord without spina bifida in 5 (4%), an association the authors consider genuine [13]. The sex ratio was 67 males to 48 females (58% and 42%) [13], 34 to 25 in a series of 59 patients [27] and about 1.6 to 1 in the GLHS review [19].

3.3. Central nervous system

The cerebellar malformation ranges from partial absence of the nodulus and vermis to complete absence of the vermis with fusion of the entire cerebellum [47]. The most frequent associated anomalies are aqueductal stenosis with hydrocephalus, fusion of the colliculi (mesencephalosynapsis), fusion of the cerebellar tonsils, agenesis of the septum pellucidum, dysgenesis of the corpus callosum, absence of the olfactory bulbs and, rarely, atypical forms of holoprosencephaly [13, 47]. In a series of 20 children, hydrocephalus with aqueductal stenosis occurred in 13 (65%), mainly through caudal stenosis; all children with stenosis had collicular fusion and all 6 with complete rhombencephalosynapsis had aqueductal stenosis [52]. A 2026 Russian review, with 72 cases from 41 publications, recorded agenesis of the septum pellucidum in 46%, hydrocephalus in 39% and corpus callosum anomalies in 37.5% [67].

In GLHS, Smith's describes ventriculomegaly, arachnoid cyst, absent septum pellucidum, dysgenesis of the corpus callosum and brainstem hypoplasia, and, occasionally, a single azygos anterior cerebral artery and lipoma of the quadrigeminal plate [1]; the lipoma was first described in a 15-year-old boy [42], and MR angiography excluded the azygos artery in Brazilian patients [56]. One boy had, in addition to severe rhombencephalosynapsis, ventriculomegaly, septal agenesis, a thin corpus callosum with an interhemispheric cyst and bilateral bipartite parietal bone [68].

The most common postnatal neurological presentation is hypotonia with motor delay, which prompts neuroimaging [13]. Truncal and gait ataxia, dysmetria, dysarthria and abnormal eye movements are frequent, but rarely limit daily life greatly [1, 13, 69]. In Smith's, central hypotonia coexists with peripheral hypertonia, spasticity and brisk reflexes; seizures are described [1]. The neurological examination may be normal in mild forms [28].

3.4. Head stereotypies, movement and vestibular function

Persistent head nodding, in a figure-of-eight or side-to-side pattern, is the most characteristic motor sign. In a series of 59 patients between 6 months and 32 years of age (mean 7.8 years), it was present in 50 (85%); it was intermittent or almost constant, increased with fatigue, excitement and reduced visual attention, and diminished with visual fixation, tactile stimulation of the face and sleep [27]. It began in the first year in 22 of 34 patients (65%), in the second in 6 (18%) and after 2 years in 6 (18%), and was observed before the diagnosis of the malformation in 31 of 39 (79%), with intervals from months to 32 years; it was not related to the severity of rhombencephalosynapsis [27]. Other stereotypies occurred in 28 of 36 (78%: hand movements, flapping, bruxism, body rocking, head banging), motor or phonic tics in 11 of 19 (58%) and obsessive-compulsive tendencies in 12 of 24 (50%) [27]. In four patients studied, all had oculomotor anomalies, and vestibular function was abnormal in the three with nodding and normal in the only one without it; the authors proposed that the figure-of-eight movement compensates for a central vestibular deficit, by activating all three semicircular canals [27]. Figure-of-eight nodding is considered highly suggestive of rhombencephalosynapsis [13].

3.5. Cognition, behaviour and mental health

Cognition ranges from profound intellectual disability to normal or superior functioning (intelligence quotient, IQ, of 130 or more) [13]. More severe rhombencephalosynapsis, holoprosencephaly and VACTERL features are associated with poorer neurodevelopment [47], but no single factor predicts the individual prognosis [13]. In non-syndromic rhombencephalosynapsis, a French series of 6 children followed at one centre for 15 years (3 with prenatal diagnosis) found a full-scale IQ between 90 and 142 in all, attention deficit hyperactivity disorder (ADHD) in 3 and mainstream schooling in all [28]. Pooling 12 publications, 28 patients with non-syndromic rhombencephalosynapsis had normal cognition in 68%, borderline in 18% and moderate to severe disability in 14%, and motor complaints absent or minimal in 72%, moderate in 16% and severe in 12% [28]. In a series of 5 children with non-syndromic rhombencephalosynapsis, all had ataxia (limiting in only one), and full-scale IQ was normal in 2 [69]. In a series of 9 children with various associated anomalies, the spectrum ranged from mild truncal ataxia with normal cognition to severe cerebral palsy with intellectual disability, without correlation with imaging [70]. In Toronto, rhombencephalosynapsis accounted for 3% (2 children) of 67 with congenital cerebellar malformations [71].

Confirmed or suspected ADHD occurred in 29 of 36 patients (81%) [27]. A 22-year-old woman with rhombencephalosynapsis had emotional reactivity and dysregulation, impulsivity and executive deficits since childhood, a profile compatible with the cerebellar cognitive affective syndrome linked to the posterior vermis and with greater vulnerability to stress [72]. In GLHS, hyperactivity, depression, self-injurious behaviour and bipolar disorder have been described in a man followed from birth to 19 years [41], bipolar spectrum symptoms with possible hypomania [56], aggressiveness with episodes of rage [42], autism spectrum disorder in a 36-month-old Georgian boy without language and with self-injury [73] and schizophrenia [74]. Smith's includes self-injurious behaviour, attention deficit, bipolar disorder, aggressiveness and impulsivity in the behavioural phenotype [1].

3.6. Scalp and skin

The alopecia associated with rhombencephalosynapsis is a focal hypotrichosis, often bilateral and symmetrical, parietal, parieto-temporal or parieto-occipital, which may contain tufts of hair; it ranges from an area of sparse hair to well-demarcated hairless areas [10]. On biopsy, the skin architecture is preserved, the follicles are variably hypoplastic and there is no inflammation or scarring; the picture is clinically and histologically equivalent to congenital triangular (temporal) alopecia, and one patient with triangular alopecia and GLHS whose brother had triangular alopecia without rhombencephalosynapsis has been described [10]. Smith's describes underdeveloped pilosebaceous structures without scarring [1]. The alopecia is present from the neonatal period [26], but is often hidden by the surrounding hair, which explains late diagnoses [44]. A 16-year-old girl was diagnosed from bilateral non-scarring parietotemporal alopecia, with rhombencephalosynapsis discovered on MRI [75], and GLHS has been proposed as a consideration in the differential diagnosis of focal congenital alopecia in dermatology [76].

3.7. Trigeminal nerve, cornea and eyes

Trigeminal anaesthesia manifests as an absent corneal reflex, facial insensitivity and recurrent facial and corneal lesions; the three patients with trigeminal anaesthesia in the 2012 cohort had recurrent bilateral corneal lesions and facial scars [1, 10]. The anatomical basis may be visible: in an infant, CT showed bilateral absence of the foramina rotunda and of the trigeminal nerve fibres [77], and in the Brazilian series MRI with high-resolution T2-weighted sequences revealed trigeminal nerve hypoplasia in 4 of 6 patients studied, all with clinical anaesthesia [11]. Hypoplasia of the trigeminal ganglia has been described as an imaging clue [78]. A child with rhombencephalosynapsis, agenesis of the trigeminal ganglion and optic coloboma without alopecia was presented as a possible variant [79].

The corneal lesions are neurotrophic: the epithelium does not heal because of loss of sensory innervation, and patients may remain symptom-free even with an ulcer [48]. A 6-year-old child with unilateral tearing for three days, without pain or inflammation, had an epithelial defect and a corneal scar; non-contact aesthesiometry showed reduced mechanical and thermal sensitivity, in vivo confocal microscopy showed absence of innervation of the right cornea, the alopecic area was insensitive and the MRI was normal [48]. Neurotrophic keratopathy has been described in a 10-month-old girl [80] and, in 2026, in a child with rhombencephalosynapsis without alopecia, with bilateral corneal hypoaesthesia, recurrent epithelial defects and progressive opacity despite lubrication, serum eye drops and topical treatment [81]. Corneal opacities are part of the founding descriptions [2, 40] and are, together with trigeminal anaesthesia, features that distinguish GLHS from MCTT [5].

In rhombencephalosynapsis, A-pattern strabismus with superior oblique overaction and, in two patients, hypoplasia of the optic nerve and chiasm have been described [82]. Smith's records strabismus, hypertelorism, downslanting palpebral fissures and, occasionally, ptosis, nystagmus and retinal detachment [1].

3.8. Skull and face

The craniofacial features of GLHS and the spectrum include brachycephaly or turribrachycephaly, a high or prominent forehead, a large anterior fontanelle, midface hypoplasia or retrusion, hypertelorism or telecanthus, downslanting palpebral fissures, a small nose with anteverted nares, a smooth philtrum, a thin upper lip and low-set, posteriorly rotated or prominent ears [1, 10, 29]. The composite morphological score in the 2012 cohort was higher in patients with alopecia (mean 51; 95% confidence interval, 95% CI, 40–60) than in those without alopecia (32; 95% CI 16–50; p = 0.03), and similar in the group with VACTERL features (51; 95% CI 31–71) [10]. Craniosynostosis, mainly lambdoid, is frequent: a Brazilian boy born to consanguineous parents had lambdoid synostosis on three-dimensional CT [45], and in the 2012 cohort there were squamosal and multisutural synostoses that were operated on [10]. Skull shape changes over time: two of the three patients with turricephaly had severe congenital hydrocephalus and macrocephaly, with acquired turricephaly, and several operated on for craniosynostosis later had a normal contour, which makes skull shape of little use as an isolated diagnostic sign [10].

3.9. Growth and endocrinology

Smith's describes mild prenatal and significant postnatal growth deficiency, microcephaly and, occasionally, growth hormone (GH) deficiency in GLHS [1]. A 19-year-old man had short stature and GH deficiency [41]. In the 2008 Brazilian series, primary GH deficiency was excluded in all patients assessed, and one patient had possible secondary deficiency due to partial hypopituitarism after severe hydrocephalus [56]. The patient in the illustrative case had growth on the 50th to 75th centiles at 6 years [19]. Short stature is therefore inconsistent and may result from hydrocephalus rather than an intrinsic defect.

3.10. Limbs, genitalia and other organs

Smith's records a hypoplastic or absent thumb, altered thenar crease, reduced mobility of the thumb interphalangeal joint, fifth-finger clinodactyly, hypoplastic radius and ulna, cubitus valgus, metatarsus adductus, hypoplastic labia, bifid uvula and gastro-oesophageal reflux [1]. In the 2012 cohort, individual findings included bilateral sensorineural hearing loss in two patients with alopecia, piriform aperture stenosis, bilateral microtia with aural atresia, idiopathic renal failure, neurofibromatosis type 1 with an NF1 variant, heart defects (atrial septal defect, ventricular septal defect, bicuspid aortic valve, tetralogy of Fallot, right-sided or hypoplastic aortic arch, total anomalous pulmonary venous return), renal agenesis, horseshoe kidney, crossed renal ectopia, posterior urethral valves and abdominal wall defect [10].

3.11. Rhombencephalosynapsis with VACTERL features

In the 2012 cohort, 14 patients (26%) had VACTERL features: one feature in 5, two in 4 and three or more in 5; the most frequent were vertebral segmentation defects (9), renal anomalies (6), cardiac anomalies (5) and preaxial polydactyly or polysyndactyly (4), followed by radial aplasia (2, one of them in a patient with thrombocytopenia-absent radius and a 1q21.1 deletion), anal atresia (1) and a retro-oesophageal cyst (1) [10]. Alopecia also occurred in this group, without statistical association with VACTERL features (p = 0.51) [10]. In the neuropathological series of 40 fetuses, 6 had VACTERL with hydrocephalus, an association considered non-random [31], and one third of pregnancies with rhombencephalosynapsis that underwent autopsy in Toronto had VACTERL-H, almost all with complete rhombencephalosynapsis [66].

3.12. Rhombencephalosynapsis with posterior holoprosencephaly and aventriculy

Two patients in the 2012 cohort had incompletely separated cerebral hemispheres, with posterior-predominant fusion, maximal in the occipital lobes, and absence of the lateral and third ventricles; both also had VACTERL features and microcephaly, and were children of mothers with pre-existing diabetes [10]. This form is distinguished from classic holoprosencephaly, with an anteroposterior gradient, and from the middle interhemispheric variant (syntelencephaly); complete aventriculy is a feature of neither [10]. Similar cases had been described by Garfinkle (an 11-year-old girl), Sergi (a 23-week fetus with alobar holoprosencephaly and aventriculy) and Kakita (a 20-week fetus with aprosencephaly), all with maternal diabetes [10]. Smith's mentions at least two patients with rhombencephalosynapsis and holoprosencephaly distinct from GLHS [1], and the French fetal series included lobar holoprosencephaly among the associated anomalies [31].

3.13. MN1 C-terminal truncation syndrome

MCTT has been described in 25 individuals with a C-terminal germline variant, de novo or inherited from a mosaic parent [5]. The frequency of the findings, compiled by GeneReviews from the two founding series, is as follows [5, 30, 49]:

Communication varies: one child spoke at 2 years and, at 14, functioned at the level of a 7-year-old; others said single words between 3 and 6 years; some communicate by gestures with up to 50 signs [5]. Most need help to write, eat or dress. Polymicrogyria may increase the risk of seizures, but the data are insufficient [5]. Skull shape is always abnormal, with dolichocephaly, turricephaly, bitemporal narrowing, plagiocephaly or macrocephaly, with or without craniosynostosis, and head circumference is normal in those with craniosynostosis; there is a risk of intracranial hypertension [5]. There are no consistent behavioural disorders beyond frustration due to limited verbal communication, and growth parameters are usually normal [5].

The face is characterised by frontal bossing in infancy and a high forehead later, midface hypoplasia, downslanting palpebral fissures, hypertelorism, exophthalmos, a short upturned nose, small low-set ears with the upper part of the pinna frequently dysplastic, a high arched palate and, sometimes, a narrow triangular maxillary arch; one individual had a submucous cleft with bifid uvula [5]. In the series of Mak and colleagues, Duane anomaly was recorded in three patients and congenital diaphragmatic hernia in two, and at least eight had no verbal language; in the three patients of Miyake and colleagues (two Japanese and one of French ancestry, aged 5, 6 and 18 years), the global delay was severe, with developmental quotients of 18 and 31 in two of them, and all had hyperphagia [6, 30, 49]. On the MRI of 11 individuals reviewed at one centre, perisylvian polymicrogyria occurred in 9 of 10, rhombencephalosynapsis in 8 of 10, persistent trigeminal artery and a prominent posterior clinoid process in 7 of 10, a thick rostral corpus callosum in 6 of 11, hypoplastic olfactory bulbs in 4 of 8, ventriculomegaly in 3 of 11 and subcortical heterotopia in 2 of 11 [5, 30]. The rhombencephalosynapsis of MCTT is partial, with foliar dysplasia, folia crossing the midline and a small or almost absent vermis [5]. The adult natural history has not been delineated: one published individual was 21 years old and an unpublished man was well at 39 [5].

3.14. Adulthood

Rhombencephalosynapsis and GLHS may be diagnosed in adulthood. A 38-year-old man was diagnosed from bilateral alopecia [83]; a 22-year-old woman was diagnosed after a first focal motor episode [24]; and a 35-year-old patient with a treatment-resistant psychiatric disorder had the rhombencephalosynapsis missed on a first MRI [67]. The oldest patient in the 2008 Brazilian series was 29 years old [56], and in the 2012 cohort there were patients aged 26, 31 and 44 years [10]. These cases show that paucisymptomatic forms exist and that prevalence based on paediatric cases underestimates the true frequency.

4. Clinical Recognition and Warning Signs

4.1. Prenatal period

Rhombencephalosynapsis should be considered in a fetus with a small transverse cerebellar diameter (severe cerebellar hypoplasia) or with a rounded cerebellum on axial views, in the second or third trimester, especially when ventriculomegaly is present [25]. Ventriculomegaly is often the initial finding and leads to sonographic suspicion, generally after 22 weeks [31, 84]. In a Cincinnati series, half of fetuses with congenital aqueductal stenosis (15 of 30) had rhombencephalosynapsis, so every fetus with aqueductal stenosis warrants a targeted assessment of the vermis [85]. There is no newborn screening for any of the entities.

4.2. Neonatal period and infancy

In the newborn, the combination of bilateral non-scarring parietal or parieto-temporal alopecia, brachyturricephaly, midface retrusion and low-set, posteriorly rotated ears should lead to brain MRI; the dysmorphic signs and bilateral alopecia are already present in the neonatal period [26, 29]. Trigeminal anaesthesia is difficult to assess in the newborn; thin-section bone-algorithm CT may show absence of the foramina rotunda and speed up the diagnosis [77]. In infancy, hypotonia with motor delay and the onset of persistent figure-of-eight or side-to-side head nodding are the usual reasons for neuroimaging [13, 27]. In MCTT, suspicion arises in the presence of intellectual disability with severe expressive language delay, hypotonia, motor delay, hearing loss and characteristic craniofacial features [5].

4.3. Child, adolescent and adult

At later ages, the diagnosis may arise from congenital focal alopecia assessed in dermatology [75, 76], from a painless corneal ulcer in ophthalmology [48], from attention deficit with mild ataxia in paediatric neurology [27], from craniosynostosis in craniofacial surgery or from an MRI requested for a seizure or psychiatric disorder in the adult [24, 67]. Neurological examination and neuroimaging may be warranted in selected patients with parietal alopecia [75].

4.4. Warning and emergency signs

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Imaging diagnosis of rhombencephalosynapsis

The diagnosis of rhombencephalosynapsis is radiological. On MRI, the midsagittal view shows a hemispheric rather than vermian configuration, with absence of the arborised appearance of the vermis; on the axial view, the white matter is continuous across the midline and the fourth ventricle is keyhole-shaped; on the coronal view, the cerebellar folia are continuous from one side to the other [10]. The dentate nuclei are fused or medialised and the fourth ventricle may be diamond-shaped [19, 24]. Aqueductal stenosis, Chiari type I malformation, abundant central cerebellar white matter on the sagittal view, a rounded fastigial point, absence of the posterior cerebellar notch and absence of the septum pellucidum or ventriculomegaly with a small cerebellum should prompt an active search for rhombencephalosynapsis [13]. Mild forms often have a normal-sized or enlarged cerebellum with superior and inferior ectopia, and severe or complete forms are associated with cerebellar hypoplasia [13].

Severity correlates with tonsillar fusion and with midbrain anomalies, and more severe rhombencephalosynapsis is associated with poorer neurodevelopment [47]. At the same institution, review of the MRI scans of patients with aqueductal stenosis identified rhombencephalosynapsis in 9% (5 of 56) [10, 47]. MRI should also document the aqueduct, the colliculi, the septum pellucidum, the corpus callosum, the olfactory bulbs, the cortex (polymicrogyria), the pituitary and the skull base, and, when trigeminal anaesthesia is suspected, the trigeminal nerves with high-resolution T2 sequences [5, 11, 47].

Chiari type II malformation may mimic partial rhombencephalosynapsis through compression of the cerebellum in a small posterior fossa; Aldinger and colleagues consider that the appearance described in spina bifida results from compression rather than true fusion, whereas a neurosurgical series from Cleveland described rhombencephalosynapsis with Chiari type I or II in 5 of 9 patients [13, 87].

5.2. Prenatal diagnosis

In a multicentre series of 62 fetuses between 12 and 37 weeks (2002–2020), complete rhombencephalosynapsis accounted for 77.4%; the cerebellum was rounded on the axial view in 72.6% and the transverse cerebellar diameter was below the 3rd centile in 87.1% [25]. Among the 22.6% with a partial form, 6.5% were severe, 6.5% anterior, 8.1% mixed and 1.6% posterior; half had normal or near-normal cerebellar morphology and 28.5% a normal transverse diameter, which makes the partial form difficult to diagnose [25]. The fourth ventricle was abnormal in 88.7%, the midbrain in 93.5% and the pons in 77.4%, and ventriculomegaly occurred in 80.6%, more severe in the complete form and with frequent parenchymal and septal disruption [25]. In Toronto, in 34 pregnancies with rhombencephalosynapsis assessed by ultrasound and MRI, more than one third had the complete form, mesencephalosynapsis, aqueductal stenosis and diencephalosynapsis were common, and fetal MRI correlated well with neuropathology as regards the grade of rhombencephalosynapsis, aqueductal stenosis and mesencephalosynapsis; a large proportion of the forms classified as complete before birth were reclassified as partial afterwards, but the aqueductal stenosis was confirmed [66].

GLHS cannot be diagnosed with certainty before birth, because alopecia and trigeminal anaesthesia cannot be assessed [26, 88]. In Lausanne, GLHS was considered "possible" before birth on the basis of the association of rhombencephalosynapsis, hydrocephalus and sonographic craniofacial anomalies (low-set, rotated ears, hypertelorism, midface hypoplasia, micrognathia, anteverted nares), confirmed at autopsy after termination at 23 weeks [88]. The first prenatal MRI of GLHS, in an Australian fetus at 21 weeks, showed rhombencephalosynapsis after ultrasound had revealed a small, abnormally shaped cerebellum; the diagnosis of GLHS was made at 6 weeks of life on the basis of the parietal alopecia [4, 20]. In another case, published in 2007, hydrocephalus was detected at 20 weeks of gestation; the boy presented at 9 months with marked developmental delay, poor weight gain and ventriculomegaly, and MRI showed rhombencephalosynapsis with primary absence of the septum pellucidum, associated with temporoparietal baldness, central hypotonia and hyperreflexia, without a family history of neurological disease [4]. In a series of 4 perinatal cases, all with initial sonographic ventriculomegaly, fetal MRI was diagnostic in 2 [84]. In an Italian database of 4568 fetal MRI scans (2005–2024), rhombencephalosynapsis was the cause of 7.5% of the 201 cases of obstructive hydrocephalus [89]. The guidelines of the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) for the screening examination and for targeted fetal neurosonography frame this assessment [90, 91]; their full text was not consulted.

5.3. Clinical criteria for Gómez-López-Hernández syndrome

There are no international consensus criteria. Three published proposals differ mainly as to whether rhombencephalosynapsis and trigeminal anaesthesia are mandatory.

Other proposals have suggested that trigeminal anaesthesia and/or partial alopecia complete the diagnosis [43] or that brachyturricephaly, rhombencephalosynapsis and bilateral alopecia suffice [73]. The Seattle cohort proposed abandoning the named syndrome in favour of a spectrum of anomalies associated with rhombencephalosynapsis [10]. In practice, the Rush 2013 criteria are the most restrictive and the Perrone 2021 criteria the most inclusive; the choice changes the case count and should be made explicit in reports and publications. Neuroimaging, by itself, does not distinguish isolated rhombencephalosynapsis from GLHS [26].

5.4. Assessment of the trigeminal nerve and the cornea

Corneal sensation is assessed by the corneal reflex, with a cotton swab or drops of saline [10], and quantitatively by aesthesiometry, including Belmonte non-contact aesthesiometry, with in vivo confocal microscopy to document innervation [48]. MRI with high-resolution T2 sequences shows hypoplasia of the nerve [11], and bone-algorithm CT shows absence of the foramina rotunda [77]. The North American consensus on neurotrophic keratopathy recommends corneal sensation testing in the presence of a persistent epithelial defect without improvement within 14 days, a recent painless epithelial defect of unknown cause and conditions involving the trigeminal nerve, and establishes diagnosis and staging by testing corneal nerve function (quantitative or qualitative) and by biomicroscopy with vital staining and measurement of the defect [33]. Sensation in the alopecic area may also be reduced [48].

5.5. Diagnosis of MN1 C-terminal truncation syndrome

There are no consensus clinical criteria. The diagnosis is established by identifying a heterozygous pathogenic or likely pathogenic variant in MN1; a variant of uncertain significance (VUS) neither establishes nor excludes the diagnosis [5]. On MRI, the atypical form of rhombencephalosynapsis with partial or complete loss of vermian landmarks and abnormal crossing of folia and white matter tracts at the midline, associated with perisylvian polymicrogyria, persistent trigeminal artery and a prominent posterior clinoid process with abnormal tissue above the posterior pituitary bright spot, is highly suggestive [5, 15]. There is no confirmatory non-molecular test, and rhombencephalosynapsis and polymicrogyria are genetically heterogeneous [15].

The approaches are sequencing of MN1 or an intellectual disability panel that includes it (some panels do not include the gene), or exome or genome sequencing, which is the most common route [5]. Deletion and duplication analysis is of little use, because the mechanism is gain of function and no causal intragenic deletions are known; deletions that include MN1 cause a different phenotype, without rhombencephalosynapsis [5]. In the two founding series, sequencing detected the variant in 24 of 24 probands [5]; this figure is the proportion of variants detectable by sequencing among patients already diagnosed, not the clinical sensitivity of sequencing in a patient with suspected disease.

5.6. Genetic strategy for rhombencephalosynapsis

The 2021 American College of Medical Genetics and Genomics (ACMG) guideline recommends considering exome or genome sequencing as a first- or second-tier test in patients with congenital anomalies with onset before 1 year or with developmental delay or intellectual disability before 18 years [32]. Applied to rhombencephalosynapsis, this strategy makes it possible to identify MCTT, the rare monogenic causes (ZIC1, EXOSC3, ADGRL2) and copy number variants (CNVs), and documents the absence of a cause in the rest [13, 32]. Microarray remains useful if the exome does not analyse copy number variants, given that non-recurrent imbalances have been described [13, 57].

The limits should appear in the report and in counselling. A negative exome does not exclude GLHS or isolated rhombencephalosynapsis, which have no known gene [11–13]. DNA from blood or saliva does not detect tissue-restricted mosaicism; the exome does not cover non-coding regions or balanced structural rearrangements, which may require genome or long-read sequencing, as in the case of the inversion near ZIC1 [13, 51]. Low-level parental mosaicism may not be detected in leucocyte DNA [5]. The report of a positive result should state the gene, the transcript with version (for example, NM_002430.3 for MN1), Human Genome Variation Society (HGVS) nomenclature at the c. and p. levels, zygosity, the class according to ACMG/AMP (Association for Molecular Pathology) criteria and the de novo or inherited origin after parental testing [5, 60]. Faced with a VUS in MN1 outside the C-terminal region, the location of the variant relative to the NMD boundary and phenotypic concordance (including MRI) are decisive.

5.7. Practical algorithm

5.8. Targeted prenatal and preimplantation diagnosis

In MCTT, once the familial variant has been identified, prenatal diagnosis and preimplantation genetic testing are possible [5]. In rhombencephalosynapsis without a molecular cause, follow-up of a subsequent pregnancy is based on fetal neurosonography and, if necessary, fetal MRI, with the limitation that the partial form may be missed [25].

6. Differential Diagnosis

6.1. Comparative table

6.2. Distinguishing Gómez-López-Hernández syndrome from MCTT

GLHS and MCTT share turricephaly, midface hypoplasia, craniosynostosis and rhombencephalosynapsis; only GLHS has trigeminal anaesthesia, scalp alopecia, corneal opacities, short stature and ataxia [5]. In MCTT, the rhombencephalosynapsis is partial, with dysplastic folia crossing the midline, and is accompanied by perisylvian polymicrogyria in 9 of 10 and persistent trigeminal artery in 7 of 10 individuals studied, findings that are not part of the GLHS picture [5]. Severe expressive language delay and hearing loss (80%) also point towards MCTT [5]. As the features of each entity may be incomplete, exome sequencing is the practical way to separate them in any patient with rhombencephalosynapsis and dysmorphism [5, 32].

6.3. Distinguishing syndromic alopecia from other congenital alopecias

The alopecia of GLHS is non-scarring, with preserved architecture and hypoplastic follicles, and is equivalent to congenital triangular alopecia [10]. The congenital scalp aplasia cutis of Finlay-Marks syndrome is a skin defect that heals in the first year, leaving an irregular surface with sparse hair, and is associated with abnormal ears and nipples [64]. Bilateral symmetrical parietal alopecia, especially with hypotonia, ataxia or head nodding, warrants MRI [75, 76].

6.4. Imaging differentials

In the posterior fossa, rhombencephalosynapsis must be distinguished from global cerebellar hypoplasia, Dandy-Walker malformation and pontocerebellar hypoplasias, and from predominantly brainstem malformations, such as pontine tegmental cap dysplasia and brainstem disconnection, in which the dominant change is the morphology of the pons and medulla; the decisive criterion is the continuity of the folia and white matter across the midline without an interposed vermis [10, 17]. A small posterior fossa with a compressed cerebellum in Chiari type II malformation may mimic a partial form [13]. Rhombencephalosynapsis has also been described in other severe malformation syndromes, such as Neu-Laxova syndrome.

7. Treatments and Risk Management Strategies

7.1. General principles and level of evidence

No entity in scope has a disease-modifying treatment, and there is no scientific society guideline dedicated to rhombencephalosynapsis or GLHS [5, 15]. Treatment is symptomatic and addresses the complications: hydrocephalus, craniosynostosis and intracranial hypertension, the ocular surface in trigeminal anaesthesia, epilepsy, neurodevelopmental and behavioural disorders, hearing loss and feeding. The recommendations in this article come from four types of sources, which should be distinguished: the MCTT GeneReviews chapter, based on expert consensus and two cohorts [5, 15]; guidelines for conditions that occur in rhombencephalosynapsis, applied by extrapolation (craniosynostosis, paediatric hydrocephalus, neurotrophic keratopathy) [33, 86, 92]; an anaesthetic recommendation dedicated to GLHS [93]; and official medicine labels, used for doses when there is no guideline dose for the condition [34, 35, 94, 95].

7.2. Hydrocephalus and aqueductal stenosis

Hydrocephalus due to aqueductal stenosis is the most frequent neurosurgical complication and determines much of the prognosis of severe forms [52, 66]. In Toronto, all 6 live births with rhombencephalosynapsis diagnosed before birth had aqueductal stenosis and required ventriculoperitoneal shunting in the first days of life (median 5 days) [66]. In Cincinnati, among 30 newborns with congenital aqueductal stenosis, all but one (97%) were shunted; in the 15 with rhombencephalosynapsis, shunting was performed at a mean of 6 days, against 55 days in the others, a difference without statistical significance (p = 0.196), and feeding assistance in the neonatal intensive care unit was needed in 53% against 20% (p = 0.128) [85]. In a neurosurgical series from Cleveland, 7 of 9 patients had symptomatic hydrocephalus, treated by endoscopic third ventriculostomy (ETV) or ventriculoperitoneal shunting, and one required foramen magnum decompression for Chiari malformation [87].

The Congress of Neurological Surgeons (CNS) guideline for paediatric hydrocephalus, published in 2014 and updated in 2020 with 41 new studies, compares shunting with ETV [96] and recommends, with level I evidence, the use of antibiotic-impregnated catheters in children who need a shunt, because they reduce infection; it added, at level III, neuroendoscopic lavage for intraventricular clots [92]. These recommendations are not specific to rhombencephalosynapsis; the choice between shunting and ETV depends on the anatomy of the aqueduct and cisterns, which in rhombencephalosynapsis may be altered by fusion of the tectum and colliculi [52, 53].

7.3. Craniosynostosis and intracranial hypertension

The updated European craniosynostosis guideline (2021), prepared by the Dutch working group within ERN CRANIO, does not address GLHS, but its recommendations apply by extrapolation to children with GLHS or MCTT and craniosynostosis [86]. In unilambdoid synostosis, it recommends screening for intracranial hypertension annually by measuring head circumference, with fundoscopy and/or OCT if the curve decelerates; in syndromic and multisutural craniosynostosis, it recommends fundoscopy and/or OCT until at least 6 years, at a frequency that, in the syndromes studied, ranges from every 4 months until 2 years (Crouzon) to annually (Muenke) [86]. Papilloedema confirms intracranial hypertension, but its absence does not exclude it before 8 years (level 3); OCT has a sensitivity of 60% and specificity of 90% for papilloedema, and of 89% and 62% for invasively measured intracranial pressure (level 2) [86]. When clinical suspicion is high, low-dose three-dimensional CT is the first imaging study (level 3); for lambdoid synostosis, the guideline does not recommend a technique or an age for surgery [86]. Intracranial hypertension is treated according to the causal factor: small intracranial volume, moderate or severe obstructive sleep apnoea, hydrocephalus or venous hypertension [86].

The combination of craniosynostosis and hydrocephalus is relevant in rhombencephalosynapsis. The guideline notes that there are no recommendations for systematic screening for hydrocephalus, proposes MRI and MR venography in the presence of risk factors (multisutural or syndromic craniosynostosis, lambdoid synostosis, a crowded posterior fossa, Chiari malformation) and states that hydrocephalus generally develops in the first 2 years [86]. As shunting runs counter to the goal of cranial expansion, the preferred approach, when the clinical picture allows, is cranial expansion first and only then shunting; posterior fossa decompression and ventriculocisternostomy are alternatives [86]. A short MRI with single-shot T2 sequences, without anaesthesia, can assess hydrocephalus [86]. In MCTT, GeneReviews recommends examination of the skull and radiographs at the initial assessment, CT if indicated, and follow-up by an oral and maxillofacial surgeon and a neurosurgeon [5].

7.4. Ocular surface and neurotrophic keratopathy

Trigeminal anaesthesia exposes the cornea to painless epithelial defects and ulcers, which may progress to opacity, perforation and visual loss without complaints [48, 81]. Prevention rests on educating parents about the susceptibility, regular ophthalmological follow-up and immediate treatment of any lesion [48]. The North American consensus on neurotrophic keratopathy (panel of 11 experts using the RAND/UCLA method, 735 scenarios, funded by Dompé) stages the disease by the Mackie classification: stage 1, epithelial changes; stage 2, persistent epithelial defect; stage 3, ulcer, melting or perforation [33]. Its application to GLHS is an extrapolation, because the panel addressed neurotrophic keratopathy of all causes and almost exclusively in adults.

Consensus classification: "optimal" corresponds to potentially optimal treatment and "appropriate" to appropriate treatment [33]. The panel also recommends treating the underlying cause and reviewing the ocular effects of systemic medicines, such as neuroleptics, antipsychotics and antihistamines [33], which is relevant in patients with GLHS medicated for behavioural disorders. In a child with rhombencephalosynapsis without alopecia, a persistent epithelial defect that had not responded to lubrication, serum eye drops and topical treatment healed rapidly with a therapeutic contact lens [81]. The limitations of the consensus are the exclusively American panel and funding by the cenegermin marketing authorisation holder [33].

7.5. Cenegermin (Oxervate®)

Cenegermin is recombinant human nerve growth factor (rhNGF), produced in Escherichia coli, with 118 amino acids; it promotes epithelial healing and corneal reinnervation [34, 35]. It is presented as an eye-drop solution at 20 µg/ml (0.002%), in daily-use multidose vials supplied in weekly cartons of 7 vials [34]. There is no guideline with a dose for the neurotrophic keratopathy of GLHS, so the reference dose is that of the label, identical in both jurisdictions: one drop in the affected eye 6 times a day, at 2-hour intervals, starting in the morning and within 12 hours, for 8 weeks [34, 35]. Contact lenses should be removed before instillation and reinserted 15 minutes later; other eye drops should be separated by at least 15 minutes, and cenegermin should be administered 15 minutes before ointments or gels [34]. The vials are stored frozen in the pharmacy, for up to 14 days in the refrigerator at home, and the opened vial should be discarded after 12 hours [34].

The US label has no contraindications; the European summary of product characteristics (SmPC) contraindicates it only in hypersensitivity [34, 35]. The most frequent adverse effects in the trials were eye pain (about 16%) and, between 1% and 10%, corneal deposits, foreign body sensation, hyperaemia, ocular inflammation, photophobia, tearing and headache; after marketing, eye irritation, blepharitis and corneal neovascularisation were reported [34]. The European SmPC recommends assessing the risk of melting or perforation and not using the medicine when immediate surgery is needed, treating ocular infection first, avoiding topical corticosteroids and eye drops with preservatives such as benzalkonium chloride, and caution in ocular cancer [35]. Eye pain is the most common complaint and, in a child with trigeminal anaesthesia, may not be reported; monitoring depends on slit-lamp examination.

Use in children with GLHS raises a regulatory divergence. The FDA label indicates cenegermin for neurotrophic keratitis, without restriction by stage, and considers safety and efficacy established in paediatrics, with additional safety data from 2 years of age [34]. The European SmPC limits the indication to moderate (persistent epithelial defect) or severe (corneal ulcer) neurotrophic keratitis in adults and states that safety and efficacy below 18 years have not been established [35]. In Portugal and the rest of the European Union, treating a child with GLHS is therefore off-label use, with the same dosage; in the USA, it is within the indication from 2 years. The North American consensus considers cenegermin optimal in stages 2 and 3 and appropriate in stage 1 [33].

7.6. Comparative regulatory status

The exact date of FDA approval of cenegermin in 2018 was not confirmed in a primary official source; the label gives only the year [34]. The centralised European authorisation is valid in Portugal. The registration and package leaflet of cenegermin, somatropin and methylphenidate in Brazil were not consulted.

7.7. Cenegermin trials

In the two trials, mean age was 61 to 65 years (18 to 95) and about 61% were women; the total was 151 patients, of whom 101 were treated with 20 µg/ml, and recurrence after healing was about 20% in NGF0212 and 14% in NGF0214 [34]. The trials did not include children with congenital trigeminal anaesthesia, and healing in a cornea without innervation since birth may differ from that in adults with acquired keratopathy; the results should not be compared indirectly with those of other interventions.

7.8. Growth hormone deficiency

GH deficiency is occasional in GLHS: it was documented in one patient [41] and considered secondary to hypopituitarism after hydrocephalus in another, primary deficiency having been excluded in the other Brazilian patients assessed [1, 56]. Somatropin is indicated only if the deficiency is demonstrated by the usual tests; there are no efficacy data in GLHS. In the absence of a specific guideline, the reference dose is that of the label for paediatric GH deficiency, applied by extrapolation: 0.16 to 0.24 mg/kg/week of somatropin (Genotropin®), divided into 6 or 7 subcutaneous injections, never intravenously, with rotation of injection sites to avoid lipoatrophy and under the supervision of a physician experienced in GH deficiency [94]. The label contraindicates somatropin in acute critical illness, active neoplasia, closed epiphyses, proliferative or severe non-proliferative diabetic retinopathy and hypersensitivity to the excipients, and points out that GH deficiency may be a sign of a pituitary tumour, which should be excluded before starting [94]. In a child with shunted hydrocephalus, pituitary assessment should take into account the possibility of secondary hypopituitarism [56].

7.9. Attention deficit hyperactivity disorder and behaviour

ADHD is common in rhombencephalosynapsis (81% in the Tully 2013 series) and in GLHS [1, 27]. There are no drug trials in rhombencephalosynapsis; treatment follows that of ADHD, which is the analogous condition, and the reference dose is that of the label, as there is no specific guideline in the material consulted. For immediate-release methylphenidate (Ritalin® in the USA), a central nervous system stimulant indicated for ADHD from 6 years of age, the label recommends starting with 5 mg twice a day (before breakfast and lunch), increasing by 5 to 10 mg per week and not exceeding 60 mg/day; in the adult, the average dose is 20 to 30 mg/day in 2 or 3 doses, 30 to 45 minutes before meals, with a maximum of 60 mg/day [95]. If there is no improvement after one month of adjustment, the medicine should be discontinued, and the dose is reduced or stopped in the event of paradoxical worsening or adverse effects [95]. Before starting, the label requires cardiac assessment (personal and family history of sudden death or ventricular arrhythmia and physical examination) and screening for motor or vocal tics and Tourette syndrome; it contraindicates the medicine in hypersensitivity and with monoamine oxidase inhibitors, current or stopped less than 14 days previously [95]. Screening for tics is particularly relevant, because 58% of patients with rhombencephalosynapsis assessed had tics [27]. The name and presentations authorised in Portugal were not checked in the national SmPC.

In MCTT, GeneReviews recommends interventions for autism spectrum disorder, including applied behaviour analysis, follow-up by a developmental paediatrician for behavioural strategies and medication (for example, for ADHD) and assessment by psychiatry or psychology in the presence of aggressiveness, self-injury or destructive behaviour [5]. The same guidance applies, by extrapolation, to GLHS, in which bipolar disorder, depression, self-injury, autism and schizophrenia have been described [41, 56, 73, 74]. A 2026 Turkish report describes drug-associated hyponatraemia in a patient with GLHS and schizophrenia; only the title was consulted, but it indicates the need to monitor electrolytes when psychotropic medicines are combined [97].

7.10. Epilepsy

Seizures are described in GLHS and in 27% of patients with MCTT [1, 5]. In MCTT, most patients with seizures had isolated events that responded to antiseizure medication; many antiseizure medicines may be effective, none has shown superiority in this condition, and treatment should be undertaken by an experienced neurologist according to standardised protocols, with caregiver education [5]. There are no data to guide the choice of an antiseizure medicine in rhombencephalosynapsis; the choice and dose follow the classification of the seizure and the epilepsy.

7.11. Multidisciplinary management in MCTT and the rhombencephalosynapsis spectrum

GeneReviews describes the North American model of developmental support: early intervention up to 3 years (occupational therapy, physiotherapy, speech and feeding therapy, infant mental health and special educators), developmental preschool from 3 to 5 years with an individualised education plan reviewed annually, follow-up by a developmental paediatrician at all ages and a transition plan in adolescence [5]. In Portugal and Brazil, the corresponding structures are the national early intervention and inclusive education systems; the logic of intervention is the same.

7.12. Anaesthesia and the perioperative period

The OrphanAnesthesia recommendations for GLHS (last modified in May 2015, reviewed by two disease experts and not by an anaesthesiologist) identify as typical surgery neurosurgery (ventriculoperitoneal shunting, cranial vault reconstruction), ophthalmic surgery for trauma and plastic surgery [93]. They recommend assessing the airway, which may be difficult because of midface retrusion, bearing in mind that hypotonia may precipitate upper airway obstruction; if the airway is difficult, induction should maintain spontaneous ventilation until intubation is secured [93]. Before anaesthesia, ventriculomegaly or hydrocephalus (excluding intracranial hypertension), the degree of trigeminal anaesthesia, the alopecia and the baseline cognitive and behavioural status should be documented, so as not to confuse these findings with postoperative complications; eye protection during positioning is essential, especially in long procedures, because the anaesthetised cornea does not protect the eye [93]. There are no known specific pharmacological implications, monitoring is individualised if there is intracranial hypertension, and day-case surgery should be performed only in institutions able to manage the complications [93]. A 7-month-old infant with GLHS underwent laparoscopic gastrostomy and frenulotomy under general anaesthesia, with a review of the perioperative implications [98, 99].

In MCTT, the persistent trigeminal artery, present in 7 of 10 patients studied, is a potential risk in skull base and pituitary surgery; MRI should identify it before these procedures [5].

7.13. Pregnancy, lactation and reproduction

In 2015, no patient with GLHS was known to have reproduced, so obstetric recommendations are speculative [93]. Six adults with rhombencephalosynapsis had 11 children, none with the malformation [13], and no patient with MCTT had known offspring in 2020 [5]. There are no data on cenegermin in pregnant women; animal studies showed no fetal effects at clinically relevant doses, and the European SmPC prefers, as a precaution, to avoid its use in pregnancy [34, 35]. There are no data on its presence in human milk, and the breastfeeding decision weighs the benefit to the mother and the infant [34]. In a woman with rhombencephalosynapsis planning pregnancy, the assessment should include the cerebrospinal fluid shunt, if any, and antiseizure and psychotropic treatment.

7.14. Transition to adulthood

The adult natural history has not been delineated for any of the entities; the oldest known adult with MCTT was 39 years old [5]. Transition should maintain neurosurgical follow-up of shunts, ophthalmological surveillance of the cornea in trigeminal anaesthesia, mental health assessment, in which emotional dysregulation and psychiatric disorder may become the main problem [67, 72], and coordination of social support [5]. GeneReviews recommends starting the transition plan in adolescence [5].

7.15. Research and developments in the last 12 months

A search of ClinicalTrials.gov on 28 October 2026 found no registered study for rhombencephalosynapsis or GLHS [100], and GeneReviews listed no trials for MCTT [5]; this absence of records does not exclude ongoing studies in other registries. The developments between November 2025 and October 2026 are of low level of evidence. In September 2026, a report was published of a child with rhombencephalosynapsis without alopecia and neurotrophic keratopathy treated with a therapeutic contact lens (case report) [81]. A neuropathological study showed that keratan sulphate proteoglycan does not participate in the pathogenesis of cerebellar dysgeneses, including rhombencephalosynapsis (human neuropathology) [54]. An Italian fetal MRI review proposed an aetiological approach to obstructive hydrocephalus, in which rhombencephalosynapsis accounted for 7.5% of cases (retrospective series) [89]. A Russian review brought together 72 cases of rhombencephalosynapsis (narrative review) [67]; a Turkish report described drug-associated hyponatraemia in a patient with GLHS and schizophrenia (case report; title only consulted) [97]; and an ISUOG conference abstract described rhombencephalosynapsis in a fetus with megalencephaly–capillary malformation–polymicrogyria syndrome (abstract; title only consulted) [65]. On the regulatory front, the US cenegermin label was revised in October 2026, and the current version maintains the indication and dosage described above [34]. The 2025 neuropathological series on mesencephalosynapsis and aqueductal stenosis falls immediately before the window [53].

7.16. Agents and situations to avoid

In trigeminal anaesthesia, eye drops with preservatives should be avoided and, during treatment with cenegermin, topical corticosteroids [33, 35]. Topical aminoglycosides are not recommended as antibiotic prophylaxis in neurotrophic keratopathy [33]. Methylphenidate requires attention to tics and prior cardiac assessment and is contraindicated with monoamine oxidase inhibitors [27, 95]. Systemic medicines with ocular effects, such as neuroleptics and antihistamines, should be reviewed when keratopathy is present [33].

8. Reproductive Options and Family Counselling

8.1. Isolated rhombencephalosynapsis and Gómez-López-Hernández syndrome

Without a known molecular cause, counselling is based on empirical data. In the literature reviewed up to 2018 there was possible recurrence in only two families, one of them disputed; there was no recurrence in at least four consanguineous families, one of them with 10 unaffected siblings [13]. In the review of 57 patients with GLHS there was no familial recurrence, and all cases appeared to be de novo [19]. Sibling recurrence is therefore low, but there is no validated numerical estimate, and the absence of recurrence in the published series does not demonstrate a zero risk. The hypothesis of autosomal recessive inheritance, raised in children of consanguineous parents [45, 46], was not supported by the family studies [13]; consanguinity was present in 4 of 57 patients with GLHS [19].

The risk to the offspring of an affected person is not quantified either. The 11 children of six adults with rhombencephalosynapsis did not have the malformation [13], a sample too small to exclude a relevant risk, especially if the cause is a de novo dominant variant or post-zygotic mosaicism, as suggested by the discordant monozygotic twins [13]. In rhombencephalosynapsis with posterior holoprosencephaly and aventriculy, the association with pre-existing maternal diabetes warrants preconception metabolic control in a subsequent pregnancy [10]. A negative exome result in the proband does not allow molecular prenatal diagnosis; surveillance of a subsequent pregnancy is by neurosonography and, if necessary, fetal MRI, with the limit that the partial form may not be detected [25].

8.2. MN1 C-terminal truncation syndrome

MCTT is autosomal dominant and, in most cases, results from a de novo variant [5]. Parental testing is recommended. If the variant is not found in either parent, it is de novo (with maternity and paternity confirmed) or results from germline or somatic and germline mosaicism in a parent; leucocyte DNA may not detect all somatic mosaicism [5]. In one family, the father of two affected siblings was mosaic, with mild features (slightly dysplastic ears and a high, narrow palate) [5, 30]. The risk to siblings is 50% if a parent is a carrier and slightly higher than that of the general population if the variant is not detected in the parents, because of the possibility of mosaicism [5]. Each child of a person with MCTT has a 50% risk of inheriting the variant, although no patient had known offspring in 2020 [5]. Once the familial variant has been identified, prenatal diagnosis and preimplantation genetic testing are possible; counselling should ideally take place before pregnancy [5].

8.3. Other monogenic causes

In the siblings with a ZIC1 variant absent in the parents, recurrence resulted from parental gonadal mosaicism, which shows that even a de novo dominant variant carries a risk of recurrence [63]. In PCH1B due to EXOSC3, inheritance is autosomal recessive, with a 25% risk for each pregnancy of a carrier couple; the c.92G>C variant is a founder variant in the Roma population [50]. Counselling of these families follows the principles for pontocerebellar hypoplasias and cerebellar hypoplasia.

8.4. Content of counselling

Counselling should explain that rhombencephalosynapsis ranges from asymptomatic forms discovered in adulthood to lethal fetal forms, that the severity of the malformation, aqueductal stenosis and associated malformations determine the prognosis [47, 66], and that most children with non-syndromic rhombencephalosynapsis have normal cognition [28]. Genetic testing of asymptomatic minors is not indicated in the entities without a known gene; in MCTT, testing of siblings is warranted only in the presence of clinical signs, because the variant is almost always de novo.

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency and what each estimate measures

The difference between the Seattle estimate (about 1/50,000) and the Orphanet class (<1/1,000,000) results from what is counted: the former estimates the prevalence of all forms in an area with a referral centre, the latter reflects the number of cases published under each label. Orphanet attributes the count of 36 GLHS cases to the 2017 Indian report [46] and that of 100 cases of isolated RES to a 2015 clinical note [101]. The Seattle cohort received about 10 new patients per year [13]. Diagnoses in adults and partial prenatal forms that are difficult to detect indicate that all these estimates underestimate the true frequency [24, 25].

9.2. Geographical distribution and populations

Patients with GLHS have been described in several regions, without a known founder effect: Mexico [40], USA [2, 12], Brazil [11], Armenia and Switzerland [44], India [46], Georgia [73], Turkey [97], Japan (one clinically suspected case) [51] and, in 2024, the first case from the Pacific region, in Hawaii [24]. MCTT has been described in two international series, one of them with patients from Japan and France, and in one case from Madrid [8, 30, 49]. The EXOSC3 c.92G>C variant of PCH1B is a founder variant in the Roma population [50].

Brazil has the largest published contribution to GLHS. In 2005, 5 of 10 patients described were Brazilian [20]; in 2008, 5 of 12 unrelated patients [56]. The Brazilian reports include the series of three patients that proposed the designation "cerebello-trigemino-dermal dysplasia" [3], two patients from 2008 (the oldest aged 29) [56], a boy born to consanguineous parents [45], the patient in the illustrative case [19] and the series of 13 patients from São Paulo, Paraná and Porto Alegre, which produced the most recent proposal of criteria [11]. The high frequency of Brazilian reports may reflect the interest of clinical genetics groups and not necessarily a higher prevalence. No Portuguese cases were found in the sources consulted, which does not demonstrate their absence.

The sex ratio tends to favour males (about 1.6:1 in GLHS and 58% males in the Seattle cohort) [13, 19], with no known explanation.

9.3. Special populations

In fetuses, the prenatal series concentrate the complete forms with hydrocephalus and VACTERL-H and have a worse prognosis [66, 84]. In adults, rhombencephalosynapsis may be discovered through a seizure, psychiatric disorder or alopecia, and the malformation may be missed on a first MRI [24, 67, 83]. Children of mothers with pre-existing diabetes constitute a risk group for the form with holoprosencephaly [10].

9.4. European reference networks and patient resources

ERN ITHACA (rare congenital malformations and rare intellectual disability) is the European reference network for the rhombencephalosynapsis spectrum and for MCTT [36]. ERN CRANIO (rare craniofacial anomalies and ear, nose and throat disorders) covers craniosynostosis and hearing loss [37], and ERN-EYE (rare eye diseases) neurotrophic keratopathy [38]. OrphanAnesthesia publishes anaesthetic recommendations for GLHS [93]. GeneReviews lists an international registry of patients with MN1 variants on the Human Disease Genes Website Series, intended to share clinical and research information [5]. The rhombencephalosynapsis research cohort of the Center for Integrative Brain Research at Seattle Children's Research Institute remains the main clinical and genetic series [13]. No patient associations specific to rhombencephalosynapsis or GLHS were identified in the sources consulted.

10. Illustrative Clinical Case

Perrone and colleagues described in 2020 a Brazilian girl, the only child of non-consanguineous parents, who was the first patient with GLHS assessed molecularly with documented prenatal exposure to misoprostol [19]. The ultrasound at 27 weeks showed posterior ventriculomegaly, enlargement of the third ventricle and vermian hypoplasia. She was born by caesarean section weighing 2850 g (10th–25th centile), 47.5 cm long (3rd–10th centile) and with a head circumference of 36.5 cm (90th–97th centile). At birth she had brachyturricephaly, a flat midface, bilateral parietal alopecia and convergent strabismus. MRI showed vermian agenesis with partial fusion of the cerebellar hemispheres and continuity of the folia, severe hydrocephalus due to aqueductal stenosis, a thin corpus callosum and fusion of the dentate nuclei with a diamond-shaped fourth ventricle (Figure 1 of the article, https://pmc.ncbi.nlm.nih.gov/articles/PMC8988015/figure/F1/). Abdominal ultrasound, echocardiogram and ophthalmological assessment were normal, and the diagnosis of GLHS was made [19].

The family was lost to follow-up until the age of 6 years, when they reported hypotonia, independent walking at 21 months and up-and-down head stereotypies, and revealed that the mother had taken two misoprostol tablets, orally and vaginally, about three weeks after conception, with moderate bleeding as the only consequence [19]. At 6 years she still had brachyturricephaly, a flat midface, bilateral parietal alopecia, downslanting palpebral fissures, low-set ears and convergent strabismus (Figure 2 of the article, lateral and frontal views, https://pmc.ncbi.nlm.nih.gov/articles/PMC8988015/figure/F2/); she weighed 19.8 kg (25th–50th centile), measured 1.22 m (50th–75th centile) and had a head circumference of 51.5 cm (50th–75th centile). She had cerebellar ataxia with an unsteady broad-based gait and impaired dynamic balance, but trigeminal function was intact (normal corneal reflexes, facial sensation, chewing and swallowing). On the Brazilian version of the Wechsler Intelligence Scale for Children (WISC-IV), full-scale IQ was 98. SNP array and exome sequencing of the proband and mother revealed no pathogenic variants [19].

The case brings together several points discussed throughout this article: prenatal suspicion from ventriculomegaly, hydrocephalus due to aqueductal stenosis, alopecia visible from birth, head stereotypies, ataxia without severe limitation, normal cognition and the absence of trigeminal anaesthesia, which, according to the Rush 2013 criteria, is compensated for by the major craniofacial findings [29]. It also shows the limits of current genetic investigation, with a negative exome [11, 13]. The association with misoprostol is an isolated observation, without demonstration of causality, and the authors do not consider it explanatory of the rhombencephalosynapsis [19]. The figure legends were consulted; the images were not. The report does not describe the treatment of the hydrocephalus, and the loss to follow-up between birth and 6 years diverges from the surveillance recommended for children with hydrocephalus and craniosynostosis [86].

A second case illustrates the adult form: a 22-year-old woman from Hawaii, with ADHD and anaemia due to menorrhagia, had after a transfusion an episode of tremor of the right arm and leg, lasting about 30 seconds, without loss of consciousness [24]. She had mild truncal ataxia, hypotonia, normal cognition and cranial nerves, no dysmorphic features, and partial parieto-temporal alopecia; MRI showed partial midline fusion of the cerebellar hemispheres with continuity of the folia, mild medialisation of the dentate nuclei and an incomplete vermis, with normal cortex, ventricles and corpus callosum (figure at https://pmc.ncbi.nlm.nih.gov/articles/PMC11268192/figure/f0005/, legend consulted). The EEG showed a poorly developed posterior rhythm and bilateral temporal theta activity without epileptiform activity, and the patient declined further studies; the authors designated the picture as "low-spectrum" GLHS [24].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

The prognosis depends mainly on the severity of the rhombencephalosynapsis, on aqueductal stenosis and hydrocephalus, and on the associated malformations (holoprosencephaly, VACTERL) [47, 66]. In non-syndromic rhombencephalosynapsis, 68% of published patients had normal cognition, 18% borderline and 14% moderate to severe disability, and 72% had no or minimal motor complaints [28]. In GLHS, Smith's states that most have significant intellectual disability, although normal cognition has been described [1]; in the more recent series, 27.9% of published patients had no disability or delay [19] and only 1 of 13 Brazilian patients had intellectual disability [11], which reflects the inclusion of mild forms. In the prenatal series the prognosis is worse: in Toronto, the 3 patients aged 2 years or more had global delay [66], and in a perinatal series of 4 cases there was one termination, two neonatal deaths and one death in the first year [84]; these series concentrate the severe forms. In MCTT, life expectancy is unknown, with one published individual aged 21 and an unpublished man well at 39 [5]. In GLHS, the oldest patients described were between 29 and 38 years old, and trigeminal anaesthesia may cause recurrent facial and corneal lesions throughout life [1, 56, 83].

11.2. Initial assessment

The assessment after diagnosis includes weight, height and head circumference; complete brain MRI (aqueduct, colliculi, septum, corpus callosum, cortex, pituitary, skull base and, if trigeminal anaesthesia is suspected, the trigeminal nerves on high-resolution T2); examination of the scalp and of corneal and facial sensation; ophthalmological assessment with slit lamp and fluorescein; craniofacial assessment with radiographs or CT if craniosynostosis is suspected; screening for VACTERL features (spine, kidneys, heart, limbs); EEG if there are seizures; assessment of development, language and behaviour; audiology; feeding assessment; and genetics clinic referral with exome or genome sequencing [5, 10, 11, 32, 33, 47]. In MCTT, dental and oral and maxillofacial assessment, a search for a submucous cleft and cardiology are added [5].

11.3. Surveillance

11.4. Prognosis with treatment

Early shunting of hydrocephalus, craniosynostosis surgery with surveillance for intracranial hypertension, corneal protection and rehabilitation are the interventions with predictable impact, but no series measures their effect in rhombencephalosynapsis; the available data describe patients already treated and do not allow the effect of the intervention to be separated from the natural history [66, 85, 86]. Healing of corneal lesions with cenegermin has been demonstrated in adults with acquired keratopathy [34], and response to a therapeutic contact lens is described in one paediatric case [81].

12. Summary and Final Considerations

Rhombencephalosynapsis is the fusion of the cerebellar hemispheres without an interposed vermis. With an estimated prevalence of about 1/50,000 in an area with a referral centre, it is more frequent than the published cases suggest, and the spectrum ranges from fetal forms with severe hydrocephalus to adults with minimal symptoms. Gómez-López-Hernández syndrome, described by Gómez in 1979 and by López-Hernández in 1982, is the best-known syndromic form: rhombencephalosynapsis with non-scarring parieto-temporal alopecia and, in a proportion of patients, trigeminal anaesthesia, brachyturricephaly and midface retrusion. Its cause is unknown; exome studies in dozens of probands have not identified a recurrent gene, and there is no basis for attributing it to chromatin-regulation genes. The Seattle cohort proposed that alopecia, the craniofacial features and trigeminal anaesthesia be viewed as anomalies of a spectrum, to which rhombencephalosynapsis with VACTERL features and rhombencephalosynapsis with posterior holoprosencephaly and aventriculy also belong.

MN1 C-terminal truncation syndrome, described in 2020, is the only well-established monogenic cause of a form of rhombencephalosynapsis: de novo variants in the terminal exon produce a stable truncated protein with gain of function, and the picture combines intellectual disability with severe expressive language delay, hearing loss, midface hypoplasia, partial rhombencephalosynapsis, perisylvian polymicrogyria and persistent trigeminal artery. Exome or genome sequencing should be requested in any patient with rhombencephalosynapsis, bearing in mind that a negative result excludes neither GLHS nor isolated rhombencephalosynapsis.

The diagnosis is radiological and classification depends on examination of the scalp, cornea and skeleton. Treatment is symptomatic and rests on neurosurgery for hydrocephalus, surveillance for intracranial hypertension according to the European craniosynostosis guideline, protection of the anaesthetised cornea, with cenegermin available for moderate or severe neurotrophic keratopathy (within the indication in the USA from 2 years and off-label in children in the European Union), and support for neurodevelopment and mental health. Most children with non-syndromic rhombencephalosynapsis have normal cognition, and the risk of recurrence in the forms without a known cause is low, with no validated numerical estimate; in MCTT, the risk follows autosomal dominant inheritance with possible parental mosaicism.

13. References

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